Method Of Treating Otic Infections With Moxifloxacin Compositions

ABSTRACT

Ophthalmic, otic and nasal compositions containing a new class of antibiotics (e.g., moxifloxacin) are disclosed. The compositions preferably also contain one or more anti-inflammatory agents. The compositions may be utilized to treat ophthalmic, otic and nasal conditions by topically applying the compositions to the affected tissues.

This application is a continuation of U.S. application Ser. No.10/715,055, filed Nov. 17, 2003, which is a continuation of U.S.application Ser. No. 10/200,868, filed Jul. 22, 2002, now U.S. Pat. No.6,716,830, which is a continuation of U.S. patent application Ser. No.09/646,797, filed Sep. 22, 2000, now abandoned, which is the NationalStage of International Application No. PCT/US99/22622, filed Sep. 29,1999, which claims benefit under 35 U.S.C. §119(e) of U.S. ProvisionalApplication Nos. 60/102,504 and 60/102,506, filed on Sep. 30, 1998.

BACKGROUND OF THE INVENTION

The present invention is directed to the provision of topical antibioticpharmaceutical compositions for the treatment of ophthalmic, otic andnasal infections, particularly bacterial infections, and to methods oftreating ophthalmic, otic and nasal infections by applying thosecompositions to the affected tissues. The compositions and methods ofthe invention are based on the use of a new class of antibiotics. Thecompositions of the present invention may also contain one or moreanti-inflammatory agents.

The use of quinolone antibiotics to treat infections represents thecurrent state of the art in the field of ophthalmic pharmaceuticalcompositions and methods of treatment. For example, a topical ophthalmiccomposition containing the quinolone ciprofloxacin is marketed by AlconLaboratories, Inc. under the name CILOXAN™ (Ciprofloxacin 0.3%)Ophthalmic Solution. The following quinolones have also been utilized inophthalmic antibiotic compositions:

Quinolone Product Manufacturer Ofloxacin OCUFLOX ™ Allergan NorfloxacinCHIBROXIN ™ Merck Lomefloxacin LOMEFLOX ™ Senju

The foregoing quinolone antibiotic compositions are generally effectivein treating ophthalmic infections, and have distinct advantages overprior ophthalmic antibiotic compositions, particularly those havingrelatively limited spectrums of antimicrobial activity, such as:neomycin, polymyxin B, gentamicin and tobramycin, which are primarilyuseful against gram negative pathogens; and bacitracin, gramicidin, anderythromycin, which are primarily active against gram positivepathogens. However, despite the general efficacy of the ophthalmicquinolone therapies currently available, there is a need for improvedcompositions and methods of treatment based on the use of antibioticsthat are more effective than existing antibiotics against key ophthalmicpathogens, and less prone to the development of resistance by thosepathogens.

There is an even greater need for effective topical compositions andmethods for treating otic and nasal infections, particularly bacterialinfections. The use of oral antibiotics to treat otic infections inchildren has limited efficacy, and creates a serious risk of pathogenresistance to the orally administered antibiotics.

Ophthalmic, otic and nasal infections are frequently accompanied byinflammation of the infected ophthalmic, otic and nasal tissues andperhaps even surrounding tissues. Similarly, ophthalmic, otic and nasalsurgical procedures that create a risk of microbial infectionsfrequently also cause inflammation of the affected tissues. Thus, thereis also a need for ophthalmic, otic and nasal pharmaceuticalcompositions that combine the anti-infective activity of one or moreantibiotics with the anti-inflammatory activity of one or more steroidor non-steroid agents in a single composition.

SUMMARY OF THE INVENTION

The invention is based on the use of a potent new class of antibioticsto treat ophthalmic, otic and nasal infections, as well as theprophylactic use of these antibiotics following surgery or other traumato ophthalmic, otic or nasal tissues. The compositions of the presentinvention may also be administered to the affected tissues duringophthalmic, otic or nasal surgical procedures to prevent or alleviatepost-surgical infection.

The compositions preferably also contain one or more anti-inflammatoryagents to treat inflammation associated with infections of ophthalmic,otic or nasal tissues. The anti-inflammatory component of thecompositions is also useful in treating inflammation associated withphysical trauma to ophthalmic, otic or nasal tissues, includinginflammation resulting from surgical procedures. The compositions of thepresent invention are therefore particularly useful in treatinginflammation associated with trauma to ophthalmic, otic or nasal tissueswherein there is either an infection or a risk of an infection resultingfrom the trauma.

Examples of ophthalmic conditions that may be treated with thecompositions of the present invention include conjunctivitis, keratitis,blepharitis, dacyrocystitis, hordeolum and corneal ulcers. Thecompositions of the invention may also be used prophylactically inconnection with various ophthalmic surgical procedures that create arisk of infection.

Examples of otic conditions that may be treated with the compositions ofthe present invention include otitis extema and otitis media. Withrespect to the treatment of otitis media, the compositions of thepresent invention are primarily useful in cases where the tympanicmembrane has ruptured or tympanostomy tubes have been implanted. Thecompositions may also be used to treat infections associated with oticsurgical procedures, such as tympanostomy, or to prevent suchinfections.

The compositions of the present invention are specially formulated fortopical application to ophthalmic, otic and nasal tissues. Thecompositions are preferably sterile, and have physical properties (e.g.,osmolality and pH) that are specially suited for application toophthalmic, otic and nasal tissues, including tissues that have beencompromised as the result of preexisting disease, trauma, surgery orother physical conditions.

DETAILED DESCRIPTION OF THE INVENTION

The antibiotics used in the compositions and methods of the presentinvention have the following formula:

wherein:

A is CH, CF, CCl, C—OCH₃, or N;

X¹ is H, halogen, NH₂, or CH₃;

R¹ is C₁ to C₃ alkyl, FCH₂CH₂, cyclopropyl or phenyl, optionally mono-,di- or tri-substituted by halogen, or A and R₁ together can form abridge of formula C—O—CH₂—CH(CH₃);

R² is H, C₁ to C₃ alkyl (optionally substituted by OH, halogen or NH₂),or 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl; and

B is a selected from the group consisting of:

wherein:

Y is O or CH₂;

R³ is C₂-C₅ alkoxyl, CH₂—CO—C₆H₅, CH₂CH₂CO₂R′, R′O₂C—CH═C—CO₂R′,CH═CH—CO₂R′ or CH₂CH₂—CN,

wherein:

R′ is H or C₁ to C₃ alkyl;

R⁴ is H, C₁ to C₃ alkyl, C₂-C₅ alkoxyl, CH₂—CO—C₆H₅, CH₂CH₂CO₂R′,R′O₂C—CH═C—CO₂R′, CH═CH—CO₂R′, CH₂CH₂—CN or5-methyl-2-oxo-1,3-dioxol-4-yl-methyl,

wherein:

R′ is H or C₁ to C₃ alkyl; and

their pharmaceutically useful hydrates and salts.

The compound Moxifloxacin is most preferred. Moxifloxacin has thefollowing structure:

Further details regarding the structure, preparation, and physicalproperties of Moxifloxacin and other compounds of formula (I) areprovided in U.S. Pat. No. 5,607,942.

The concentrations of the antibiotics of formula (I) in the compositionsof the present invention will vary depending on the intended use of thecompositions (e.g., treatment of existing infections or prevention ofpost-surgical infections), and the relative antimicrobial activity ofthe specific antibiotic selected. The antimicrobial activity ofantibiotics is generally expressed as the minimum concentration requiredto inhibit the growth of a specified pathogen. This concentration isalso referred to as the “minimum inhibitory concentration” or “MIC”. Theterm “MIC90” refers to the minimum concentration of antibiotic requiredto inhibit the growth of ninety percent (90%) of the strains of aspecies. The concentration of an antibiotic required to totally kill aspecified bacteria is referred to as the “minimum bactericidalconcentration” or “MBC”. The minimum inhibitory concentration ofMoxifloxacin for several bacteria commonly associated with ophthalmic,otic and nasal infections are provided in the following table:

Microorganism MIC₉₀ S. aureus/methicillin sensitive 0.13 S.aureus/methicillin resistant 4.0 S. aureus/quinolone resistant 4.0 S.epidermidis/methicillin sensitive 0.25 S. epidermidis/methicillinresistant 4.0 S. pneumoniae/penicillin sensitive 0.25 S.pneumoniae/penicillin resistant 0.25 P. aeruginosa 8.0 H.influenzae/.beta.-lactamase positive 0.06 H influenzae/.beta.lactamasenegative 0.06

All of the foregoing concentrations are expressed as micrograms permilliliter (“mcg/ml”).

The appropriate antibiotic concentration for ophthalmic compositionswill generally be an amount of one or more antibiotics of formula (I)sufficient to provide a concentration in the aqueous humor and lacrimalfluid of the eye equal to or greater than the MIC90 level for theselected antibiotic(s), relative to gram-negative and gram-positiveorganisms commonly associated with ophthalmic infections. Theappropriate concentration for otic and nasal compositions will generallybe an amount of one or more antibiotics of formula (I) sufficient toprovide a concentration in the infected tissues equal to or greater thanthe MIC90 level for the selected antibiotic(s), relative togram-negative and gram-positive organisms commonly associated with oticor nasal infections. Such amounts are referred to herein as “anantimicrobial effective amount”. The compositions of the presentinvention will typically contain one or more compounds of formula (I) ina concentration of from about 0.1 to about 1.0 percent by weight (“wt.%”) of the compositions.

The compositions of the present invention may also contain one or moreanti-inflammatory agents. The anti-inflammatory agents utilized in thepresent invention are broadly classified as steroidal or non-steroidal.The preferred steroidal anti-inflammatory agents are glucocorticoids.

The preferred glucocorticoids for ophthalmic and otic use includedexamethasone, loteprednol, rimexolone, prednisolone, fluorometholone,and hydrocortisone. The preferred glucocorticoids for nasal use includemometasone, fluticasone, beclomethasone, flunisolide, triamcinolone andbudesonide.

The dexamethasone derivatives described in U.S. Pat. No. 5,223,493(Boltralik) are also preferred steroidal anti-inflammatory agents,particularly with respect to compositions for treating ophthalmicinflammation. The following compounds are especially preferred:

These compounds are referred to herein as “21-ether derivatives ofdexamethasone”. The 21-benzyl ether derivative (i.e., compound AL-2512)is particularly preferred.

The preferred non-steroidal anti-inflammatory agents are: prostaglandinH synthetase inhibitors (Cox I or Cox II), also referred to ascyclooxygenase type I and type II inhibitors, such as diclofenac,flurbiprofen, ketorolac, suprofen, nepafenac, amfenac, indomethacin,naproxen, ibuprofen, bromfenac, ketoprofen, meclofenamate, piroxicam,sulindac, mefanamic acid, diflusinal, oxaprozin, tolmetin, fenoprofen,benoxaprofen, nabumetome, etodolac, phenylbutazone, aspirin,oxyphenbutazone, NCX-4016, HCT-1026, NCX-284, NCX-456, tenoxicam andcarprofen; cyclooxygenase type II selective inhibitors, such as NS-398,vioxx, celecoxib, P54, etodolac, L-804600 and S-33516; PAF antagonists,such as SR-27417, A-137491, ABT-299, apafant, bepafant, minopafant,E-6123, BN-50727, nupafant and modipafant; PDE IV inhibitors, such asariflo, torbafylline, rolipram, filaminast, piclamilast, cipamfylline,CG-1088, V-11294A, CT-2820, PD-168787, CP-293121, DWP-205297, CP-220629,SH-636, BAY-19-8004, and roflumilast; inhibitors of cytokine production,such as inhibitors of the NFkB transcription factor; or otheranti-inflammatory agents known to those skilled in the art.

The concentrations of the anti-inflammatory agents contained in thecompositions of the present invention will vary based on the agent oragents selected and the type of inflammation being treated. Theconcentrations will be sufficient to reduce inflammation in the targetedophthalmic, otic or nasal tissues following topical application of thecompositions to those tissues. Such an amount is referred to herein as“an anti-inflammatory effective amount.” The compositions of the presentinvention will typically contain one or more anti-inflammatory agents inan amount of from about 0.01 to about 1.0 wt. %.

The compositions are typically administered to the affected ophthalmic,otic or nasal tissues by topically applying one to four drops of asterile solution or suspension, or a comparable amount of an ointment,gel or other solid or semisolid composition, one to four times per day.However, the compositions may also be formulated as irrigating solutionsthat are applied to the affected ophthalmic, otic or nasal tissuesduring surgical procedures.

The ophthalmic, otic and nasal compositions of the present inventionwill contain one or more compounds of formula (I) and preferably one ormore anti-inflammatory agents, in pharmaceutically acceptable vehicles.The compositions will typically have a pH in the range of 4.5 to 8.0.The ophthalmic compositions must also be formulated to have osmoticvalues that are compatible with the aqueous humor of the eye andophthalmic tissues. Such osmotic values will generally be in the rangeof from about 200 to about 400 milliosmoles per kilogram of water(“mOsm/kg”), but will preferably be about 300 mOsm/kg.

Ophthalmic, otic and nasal pharmaceutical products are typicallypackaged in multidose form. Preservatives are thus required to preventmicrobial contamination during use. Suitable preservatives include:polyquatemium-1, benzalkonium chloride, thimerosal, chlorobutanol,methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium,sorbic acid, or other agents known to those skilled in the art. The useof polyquatemium-1 as the antimicrobial preservative is preferred.Typically such preservatives are employed at a level of from 0.001% to1.0% by weight.

The solubility of the components of the present compositions may beenhanced by a surfactant or other appropriate co-solvent in thecomposition. Such co-solvents include polysorbate 20, 60, and 80,polyoxyethylene/polyoxypropylene surfactants (e.g., Pluronic F-68, F-84and P-103), cyclodextrin, or other agents known to those skilled in theart. Typically such co-solvents are employed at a level of from 0.01% to2% by weight.

The use of viscosity enhancing agents to provide the compositions of theinvention with viscosities greater than the viscosity of simple aqueoussolutions may be desirable to increase ocular absorption of the activecompounds by the target tissues or increase the retention time in theeye, ear or nose. Such viscosity building agents include, for example,polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose,hydroxy propyl cellulose or other agents know to those skilled in theart. Such agents are typically employed at a level of from 0.01% to 2%by weight.

The following examples are provided to further illustrate theophthalmic, otic and nasal compositions of the present invention.

EXAMPLE 1

Ophthalmic/Otic/Nasal Solution Ingredient Amount (wt. %) Moxifloxacin0.35 Sodium Acetate 0.03 Acetic Acid 0.04 Mannitol 4.60 EDTA 0.05Benzalkonium Chloride 0.006 Water q.s. 100

EXAMPLE 2

Ophthalmic/Otic/Nasal Suspension Ingredient Amount (wt. %) Moxifloxacin0.3 Dexamethasone, Micronized USP 0.10 Benzalkonium Chloride 0.01Edetate Disodium, USP 0.01 Sodium Chloride, USP 0.3 Sodium Sulfate, USP1.2 Tyloxapol, USP 0.05 Hydroxyethylcellulose 0.25 Sulfuric Acid and/orSodium q.s. for pH adjustment Hydroxide, NF to 5.5 Purified Water, USPq.s. to 100

EXAMPLE 3

Ophthalmic Ointment Ingredient Amount (wt. %) Moxifloxacin 0.35 MineralOil, USP 2.0 White petrolatium, USP q.s 100

EXAMPLE 4

Ophthalmic Ointment Ingredient Amount (wt. %) Moxifloxacin 0.3Fluorometholone Acetate, USP 0.1 Chlorobutanol, Anhydrous, NF 0.5Mineral Oil, USP 5 White Petrolatum, USP q.s. 100

The invention has been described herein by reference to certainpreferred embodiments. However, as obvious variations thereon willbecome apparent to those skilled in the art, the invention is not to beconsidered as limited thereto.

1. A topical otic pharmaceutical composition comprising an antimicrobialeffective amount of one or more compounds of the formula:

wherein: A is CH, CF, CCl, C—OCH₃, or N; X¹ is H, halogen, NH₂, or CH₃;R¹ is C₁ to C₃ alkyl, FCH₂CH₂, cyclopropyl or phenyl, optionally mono-,di- or tri-substituted by halogen, or A and R₁ together can form abridge of formula C—O—CH₂—CH(CH₃); R² is H, C₁ to C₃ alkyl (optionallysubstituted by OH, halogen or NH₂), or5-methyl-2-oxo-1,3-dioxol-4-yl-methyl; and B is a selected from thegroup consisting of:

wherein: Y is O or CH₂; R³ is C₂-C₅ alkoxyl, CH₂—CO—C₆H₅, CH₂CH₂CO₂R′,R′O₂C—CH═C—CO₂R′, CH═CH—CO₂R′ or CH₂CH₂—CN, wherein: R′ is H or C₁ to C₃alkyl; R⁴ is H, C₁ to C₃ alkyl, C₂-C₅ alkoxyl, CH₂—CO—C₆H₅, CH₂CH₂CO₂R′,R′O₂C—CH═C—CO₂R′, CH═CH—CO₂R′, CH₂CH₂—CN or5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, wherein: R′ is H or C₁ to C₃alkyl; and their pharmaceutically useful hydrates and salts; and apharmaceutically acceptable vehicle therefor.
 2. A topical compositionaccording to claim 1, wherein the composition further comprises ananti-inflammatory effective amount of a steroidal or non-steroidalanti-inflammatory agent.
 3. A topical composition according to claim 2,wherein the anti-inflammatory agent comprises a glucocorticoid.
 4. Atopical composition according to claim 3, wherein the glucocorticoid isselected from the group consisting of dexamethasone, rimexolone,prednisolone, fluorometholone, hydrocortisone, mometasone, fluticasone,beclomethasone, flunisolide, triamcinolone and budesonide.
 5. A topicalcomposition according to claim 2, wherein the anti-inflammatory agentcomprises a non-steroidal agent selected from the group consisting ofprostaglandin H synthetase inhibitors, PAF antagonists, and PDE IVinhibitors.
 6. A topical composition according to claim 2, wherein thecompound of formula (I) comprises moxifloxacin or a pharmaceuticallyuseful hydrate or salt thereof.
 7. A topical composition according toclaim 6, wherein the anti-inflammatory agent comprises dexamethasone. 8.A topical composition according to claim 6, wherein theanti-inflammatory agent comprises nepafenac.
 9. A topical compositionaccording to any one of claims 6, 7 or 8 wherein the compositioncontains moxifloxacin or a pharmaceutically useful hydrate or saltthereof at a concentration of 0.1 to 1.0 wt. %.
 10. A topicalcomposition according to any one of claims 6, 7 or 8, wherein thecomposition contains moxifloxacin or a pharmaceutically useful hydrateor salt thereof at a concentration of about 0.35 wt. %.
 11. A topicalcomposition according to any one of claims 6, 7 or 8, wherein thecomposition contains moxifloxacin or a pharmaceutically useful hydrateor salt thereof at a concentration of 0.35 to 1 wt. %.
 12. A topicalotic pharmaceutical composition comprising an antimicrobial effectiveamount of moxifloxacin or a pharmaceutically useful hydrate or saltthereof, and a pharmaceutically acceptable vehicle therefor.
 13. Atopical composition according to claim 12, wherein the compositioncontains moxifloxacin or a pharmaceutically useful hydrate or saltthereof at a concentration of 0.1 to 1.0 wt. %.
 14. A method of treatingor preventing otic infections, which comprises topically applying atherapeutically effective amount of the composition of claim 1 to theaffected otic tissue.
 15. A method of treating or preventing oticinfections and attendant inflammation, which comprises topicallyapplying a therapeutically effective amount of the composition of claim2 to the affected otic tissue.
 16. A method according to claim 15,wherein the compound of formula (I) comprises moxifloxacin or apharmaceutically useful hydrate or salt thereof.
 17. A method accordingto claim 16, wherein the anti-inflammatory agent comprisesdexamethasone.
 18. A method according to claim 16, wherein theanti-inflammatory agent comprises nepafenac.
 19. A method according toany one of claims 14-18, wherein the composition contains moxifloxacinor a pharmaceutically useful hydrate or salt thereof at a concentrationof 0.1 to 1.0 wt. %.
 20. A method according to any one of claims 14-18,wherein the composition contains moxifloxacin or a pharmaceuticallyuseful hydrate or salt thereof at a concentration of 0.35 to 1 wt. %.